CHEMISTRY of NICOTINE PHARMACOLOGY NICOTINE ABSORPTION: BUCCAL (ORAL) MUCOSA NICOTINE ABSORPTION. NICOTINE PHARMACOLOGY and PRINCIPLES of ADDICTION
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1 ICOTIE PHARMACOLOGY and PRICIPLES of ADDICTIO ICOTIE ADDICTIO U.S. Surgeon General s Report (1988) Cigarettes and other forms of tobacco are addicting. icotine is the drug in tobacco that causes addiction. The pharmacologic and behavioral processes that determine tobacco addiction are similar to those that determine addiction to drugs such as heroin and cocaine. U.S. Department of Health and Human Services. (1988). The Health Consequences of Smoking: icotine Addiction. A Report of the Surgeon General. CHEMISTRY of ICOTIE H Pyrrolidine ring Pyridine ring CH 3 icotiana tabacum atural liquid alkaloid Colorless, volatile base pk a = 8.0 PHARMACOLOGY Pharmacokinetics Effects of the body on the drug Absorption Distribution Metabolism Excretion Pharmacodynamics Effects of the drug on the body ICOTIE ABSORPTIO Absorption is ph dependent In acidic media Ionized poorly absorbed across membranes In alkaline media onionized well absorbed across membranes At physiologic ph ( ), ~31% of nicotine is unionized At physiologic ph, nicotine is readily absorbed. ICOTIE ABSORPTIO: BUCCAL (ORAL) MUCOSA The ph inside the mouth is 7.0. Acidic media (limited absorption) Cigarettes Alkaline media (significant absorption) Pipes, cigars, spit tobacco, oral nicotine products Beverages can alter ph, affect absorption. 1
2 ICOTIE ABSORPTIO: SKI and GASTROITESTIAL TRACT icotine is readily absorbed through intact skin. icotine is well absorbed in the small intestine but has low bioavailability (30%) due to firstpass hepatic metabolism. ICOTIE ABSORPTIO: LUG icotine is distilled from burning tobacco and carried in tar droplets. icotine is rapidly absorbed across respiratory epithelium. Lung ph = 7.4 Large alveolar surface area Extensive capillary system in lung ICOTIE DISTRIBUTIO icotine reaches the brain within 11 seconds. Plasma nicotine (ng/ml) Venous Arterial Minutes after light-up of cigarette Henningfield et al. (1993). Drug Alcohol Depend 33: ICOTIE METABOLISM 70 80% cotinine H 10 20% excreted unchanged in urine CH 3 ~ 10% other metabolites Metabolized and excreted in urine Adapted and reprinted with permission. Benowitz et al. (1994). J Pharmacol Exp Ther 268: ICOTIE EXCRETIO Half-life icotine t ½ = 2 hr Cotinine t ½ = 19 hr Excretion Occurs through kidneys (ph dependent; with acidic ph) Through breast milk ICOTIE PHARMACODYAMICS icotine binds to receptors in the brain and other sites in the body. Cardiovascular system Gastrointestinal system Other: euromuscular junction Sensory receptors Other organs Central nervous system Exocrine glands Adrenal medulla Peripheral nervous system icotine has predominantly stimulant effects. 2
3 ICOTIE PHARMACODYAMICS (cont d) EUROCHEMICAL and RELATED EFFECTS of ICOTIE Central nervous system Pleasure Arousal, enhanced vigilance Improved task performance Anxiety relief Other Appetite suppression Increased metabolic rate Skeletal muscle relaxation Cardiovascular system Heart rate Cardiac output Blood pressure Coronary vasoconstriction Cutaneous vasoconstriction I C O T I E Dopamine orepinephrine Acetylcholine Glutamate Serotonin β-endorphin GABA Pleasure, reward Arousal, appetite suppression Arousal, cognitive enhancement Learning, memory enhancement Mood modulation, appetite suppression Reduction of anxiety and tension Reduction of anxiety and tension Benowitz. (1999). icotine Tob Res 1(Suppl):S159 S163. WHAT IS ADDICTIO? BIOLOGY of ICOTIE ADDICTIO: ROLE of DOPAMIE Compulsive drug use, without medical purpose, in the face of negative consequences icotine stimulates dopamine release Pleasurable feelings icotine addiction is not just a bad habit. Discontinuation leads to withdrawal symptoms. Alan I. Leshner, Ph.D. Former Director, ational Institute on Drug Abuse ational Institutes of Health Repeat administration Tolerance develops Prefrontal cortex DOPAMIE REWARD PATHWAY Dopamine release CHROIC ADMIISTRATIO of ICOTIE: EFFECTS on the BRAI Human smokers have increased nicotine receptors in the prefrontal cortex. High ucleus accumbens Ventral tegmental area Stimulation of nicotine receptors icotine enters brain Low onsmoker Smoker Image courtesy of George Washington University / Dr. David C. Perry Perry et al. (1999). J Pharmacol Exp Ther 289:
4 ICOTIE PHARMACODYAMICS: WITHDRAWAL EFFECTS ICOTIE ADDICTIO CYCLE Depression Insomnia Irritability/frustration/anger Anxiety Difficulty concentrating Restlessness Increased appetite/weight gain Decreased heart rate Cravings* * ot considered a withdrawal symptom by DSM-IV criteria. Most symptoms peak hr after quitting and subside within 2 4 weeks. HADOUT American Psychiatric Association. (1994). DSM-IV. Hughes et al. (1991). Arch Gen Psychiatry 48: Hughes & Hatsukami. (1998). Tob Control 7: Reprinted with permission. Benowitz. (1992). Med Clin Am 2: ICOTIE ADDICTIO Tobacco users maintain a minimum serum nicotine concentration in order to Prevent withdrawal symptoms Maintain pleasure/arousal Modulate mood Users self-titrate nicotine intake by Smoking/dipping more frequently Smoking more intensely Obstructing vents on low-nicotine brand cigarettes ASSESSIG ICOTIE DEPEDECE Fagerström Test for icotine Dependence (FTD) Developed in 1978 (8 items); revised in 1991 (6 items) Most common research measure of nicotine dependence; sometimes used in clinical practice Responses coded such that higher scores indicate higher levels of dependence Scores range from 0 to 10; score of greater than 5 indicates substantial dependence HADOUT Heatherton et al. (1991). British Journal of Addiction 86: FACTORS COTRIBUTIG to TOBACCO USE TOBACCO DEPEDECE: A 2-PART PROBLEM Environment Tobacco advertising Physiology Genetic predisposition Tobacco Dependence Conditioned stimuli Social interactions Tobacco Use Coexisting medical conditions Physiological The addiction to nicotine Treatment Behavioral The habit of using tobacco Treatment Pharmacology Alleviation of withdrawal symptoms Weight control Pleasure Medications for cessation Behavior change program Treatment should address the physiological and the behavioral aspects of dependence. 4
5 ICOTIE PHARMACOLOGY and ADDICTIO: SUMMARY Tobacco products are effective delivery systems for the drug nicotine. icotine is a highly addictive drug that induces a constellation of pharmacologic effects. icotine activates the dopamine reward pathway in the brain, which reinforces continued tobacco use. Tobacco users who are dependent on nicotine selfregulate tobacco intake to maintain pleasurable effects and prevent withdrawal. ICOTIE PHARMACOLOGY and ADDICTIO: SUMMARY (cont d) icotine dependence is a form of chronic brain disease. Tobacco use is a complex disorder involving the interplay of the following: Pharmacology of nicotine (pharmacokinetics and pharmacodynamics) Environmental factors Physiologic factors Treatment of tobacco use and dependence requires a multifaceted treatment approach. 5
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